Fosgonimeton Small Molecule Therapy for Alzheimer’s Fails to Meet Study Endpoints

Athira Pharma (Bothwell, WA) reported results from the LIFT-AD clinical trial revealing that it’s investigational drug, fosgonimeton (ATH-1017), did not meet the study’s primary or key secondary endpoints as a treatment for mild to moderate Alzheimer disease (AD).

While treatment with fosgonimeton was associated with improved results on the cognition (Alzheimer’s Disease Assessment Scale-Cognitive Subscale [ADAS-Cog11]) and function (Alzheimer’s Disease Cooperative Study-Activities of Daily Living 23-item version [ADCS-ADL23]) components of the primary endpoint, Global Statistical Test (GST) score at 26 weeks, compared with placebo, the findings did not reach statistical significance. In some participant subgroups, such as those who were carriers of apolipoprotein E ε4 (APOE ε4), treatment with fosgonimeton resulted in improvements or stabilization in ADAS-Cog11 scores compared with those receiving placebo.

LIFT-AD is a phase 2/3 randomized, double-blind, placebo-controlled trial evaluating once-daily subcutaneous injections of fosgonimeton 40 mg vs placebo in 315 treatment-free participants aged 55 to 85 years with mild to moderate AD.

At 26 weeks, primary and secondary endpoint data favored fosgonimeton over placebo but did not reach statistical significance:

• Participants treated with fosgonimeton showed a -0.08 change in GST scores favoring the agent over placebo (P=.70).
• Treatment with fosgonimeton resulted in a change of -1.09 in ADAS-Cog11 vs -0.39 for placebo, a difference of -0.70 favoring fosgonimeton (P=.35).
• Treatment with fosgonimeton  resulted in an improvement of 0.65 in ADCS-ADL23 vs a decline of -0.02 in the placebo group (P=.61).
• Participants with moderate AD treated with fosgonimeton (n=61) showed improvement in their ADAS-Cog11 scores vs those taking placebo (n=70), with a delta of -1.16 (P=.39).
• Participants with the APOE ε4 genotype treated with fosgonimeton (n=74) maintained their ADAS-Cog11 score, while those receiving placebo (n=74) declined, with a delta of -1.07 (P=.33).

Fosgonimeton had a favorable safety profile and was generally well tolerated. Additionally, biomarker measurements obtained at week 26, including neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and plasma phosphorylated tau217 (p-tau217), plasma phosphorylated tau181 (p-tau181), and the ratio of Aβ42/Aβ40 showed improvements favoring fosgonimeton over placebo. Participants treated with fosgonimeton showed a decrease of -0.12 pg/mL plasma levels of p-tau217 vs placebo.

“While the trial did not meet its primary endpoint, the biomarker and subgroup data are intriguing and remarkably consistent not only across endpoints but also with our understanding of fosgonimeton’s neuroprotective mechanism of action,” said Anton P. Porsteinsson, MD, LIFT-AD Investigator and Director of the University of Rochester Alzheimer’s Disease Care, Research, and Education Program (AD-CARE).